tbuckley/cabot-search huggingface dataset:
P18.06.B ETS-Transcription Factor inhibitors are effective in<i>TERT</i> promoter mutated meningioma cells in vitro
Authors: K Neumayer, L Kastler, M Laaber, C Roschger, S Lenz, D Lötsch-Gojo, W Berger, A Gruber, S Spiegl-Kreinecker
Journal: Neuro-Oncology (2022)

Abstract Background TERT promoter mutations in meningiomas were recently found to be strongly prognostic and associated with malignant progression and risk of recurrence. As result, the mutation in the TERT promoter generates a binding site for E twenty-six (ETS) transcription factors. Consequently, ETS-transcription factor inhibition might represent a novel strategy to impede meningioma growth. In a prior study we could demonstrate effectiveness of the ETS-transcription factor inhibitor YK-4-279 in TERT promoter mutant meningiomas. Recently, TK216 the clinical derivative of YK-4-279 was developed. Therefore, we aimed to clarify whether TK216 might have an increased effect as compared to YK-4-279 in TERT promoter mutated meningioma cells in vitro. Methods A meningioma-derived cell line (BTL695) generated from a TERT promoter mutated (C228T) anaplastic meningioma served as cell model for the experiments. BTL695 was characterized by high telomerase activity and TERT mRNA expression as analysed by the TRAP assay and RT-PCR, respectively. Genomic aberrations were verified using Ion Torrent Oncomine Comprehensive Assay v3-based next-generation sequencing (NGS). The sensitivity of BTL695 to YK-4-279 and TK216 was determined using an MTT-based viability assay (EZ4U). To elucidate the effectiveness of TK216 on cell cycle and apoptosis, cells were stained with PI and annexin V, respectively, and measured by flow cytometry. The effect of TK216 on the protein expression of the cleaved poly(ADP-ribose) polymerase-1 (PARP-1), indicative for apoptosis, was investigated by western blot. Additionally, a TK216-resistant cell model (BTL695res) was generated and analysed by NGS. Results BTL695 was significantly more sensitive to TK216 as compared to YK-4-279 (p&amp;lt;0.0001) characterized by the distinctly lower IC50 value of TK216 exposed cells (0.7 µM TK216; 1.6 µM YK-4-279). Flow cytometry analysis revealed a TK216 induced G2M cell cycle arrest and increased apoptosis rate, which was additionally verified by the expression of cleaved PARP-1 expression using western blot. Genomic aberrations were found in 18 genes including NF2, CDKN2A/B, ARID1A and PTEN. Interestingly, although the majority of genomic alterations was persistent in the TK216 resistant cell model, a p53 mutation was newly acquired as compared to the parental cell line. Conclusion In summary, our results indicate that ETS transcription factor inhibition by TK216 exerts antitumour activity in our TERT promoter mutant meningioma cell model. Additionally, the sensitivity against TK216 is superior to YK-4-279 and therefore TK216 may represent a promising new therapeutic option for patients with aggressive, TERT promoter mutated meningioma.
P08.05.B Communication in the context of glioblastoma treatment: what matters most to patients and caregivers
Authors: F W Boele, S Butler, E Nicklin, L Pointon, S C Short, L Murray
Journal: Neuro-Oncology (2022)

Abstract Background Given the poor prognosis of glioblastoma, with short survival times regardless of treatment, it is critical that the benefits and risks of treatments are clearly discussed with patients and family caregivers. The respective value of quantity versus quality of life varies for each individual. Yet, effective communication can be complicated by emotional responses following diagnosis, patients’ neurocognitive deficits, and sometimes, lower health literacy. We aimed to investigate patient and caregiver experiences and preferences around glioblastoma treatment communication. Material and Methods Semi-structured qualitative interviews were conducted with adult glioblastoma patients and their caregivers, interviewed as dyads or individuals. Purposive sampling was used to capture views across the entire disease trajectory. Interviews were recorded, transcribed verbatim, and analysed for common themes. Analysis is ongoing and will be completed by June 2022, with preliminary findings described below. Results In total, 15 glioblastoma patients and 13 caregivers took part, 8 as dyads. Five main themes were found. 1) Communication experiences. A rush to get treatment underway can limit adequate communication. Patients and caregivers described that risks of treatment were clearly explained, but perceived it as ‘the only option’. 2) Communication preferences. Balanced and sensitive communication of prognostic information was desired, with uncertainty providing hope as well as being a burden. Patients and caregivers can have different information and support needs, requiring separate and proactive communication. 3) What matters most. Participants valued feeling involved, having clear and reliable information and support from the treatment team, and developing a personable relationship. In terms of treatment goals, they valued extending life with good quality of life. 4) Decision-making. Participants emphasised the importance of being involved in decisions, involving caregivers, and following treatment team advice. While faced with extremely limited treatment options, they valued having a sense of control over declining, pausing or stopping treatment. 5) Impact of Covid-19. In general, patients described limited impact of the measures taken during the pandemic (e.g., masks, telephone consultations), whilst caregivers highlighted specific issues around not being able to support patients in emergencies, expressing/reading nonverbal cues, or fully participating in telephone consultations. Conclusion Glioblastoma patients and caregivers value sensitive, comprehensive and comprehensible communication around treatment risks and benefits, and supportive care. Involving and supporting caregivers is critical.
P15.02.B Spatial habitat analysis in high-grade gliomas combining perfusion, diffusion, and hypoxia features derived from multiparametric MRI and 18F-FAZA PET
Authors: M Bailo, N Pecco, M Callea, P Scifo, F Gagliardi, F Fallanca, M Picchio, P Mortini, A Falini, A Castellano
Journal: Neuro-Oncology (2022)

Abstract Background Heterogeneity represents one of the main issues in high-grade gliomas (HGGs) management and presumably is the key to understanding treatment failure. Spatial habitat imaging embodies a novel, non-invasive method to cluster different tumor biological microenvironments and characterize intratumoral heterogeneity through a quantitative radiomic approach. So far, habitat imaging has been chiefly explored on morphological magnetic resonance imaging (MRI): the aim of our study was to evaluate this technique on advanced imaging techniques as perfusion (PWI) and diffusion (dMRI) MRI, as well as 18F-FAZA PET, to subdivide the tumor into different biological compartments. Materials and Methods A preoperative PWI, dMRI, and 18F-FAZA PET acquisition was obtained in 17 HGG patients to assess intratumoral vascularization, cellularity, and hypoxia, respectively. A tumor mask was created including contrast-enhancing/necrotic regions on T1 imaging and surrounding FLAIR hyperintensity, and each parametric map (plasma volume from dynamic contrast-enhanced PWI, mean diffusivity from diffusion tensor imaging, and standardized uptake value from 18F-FAZA PET) underwent OTSU’s binary clustering by grouping together voxels with high and low-intensity values. Cluster intersections were then generated by combining all possible high and low-intensity regions of each map, and the final habitat map was composed. Habitats’ quantitative features, spatial distribution, and histopathological characteristics were analyzed. Results The eight habitats generated were carefully inspected, and their distribution pattern, in relation to morphological landmarks (as contrast-enhancing, necrotic, infiltrative and edematous areas), showed an excellent reproducibility among different HGGs, offering complementary data to conventional imaging. A consistent correlation was noted between each habitat’s awaited microenvironment and the corresponding histopathological characteristics among the ten patients for whom precise coordinates of stereotactic biopsies were available. Clusters considered more aggressive were more represented in WHO grade IV (vs. grade III) tumors. The habitat possibly representing edematous areas was significantly larger in IDH-1 wild-type (vs. IDH-1 mutated) tumors. Conclusions: PET and MRI hypoxia, perfusion, and tissue diffusion habitat maps proved an excellent reproducibility among HGGs and correlation with expected histopathological features, making it a way to characterize intratumoral heterogeneity. However, further study is needed to elucidate clinical implications and confirm the spatio-temporal evolution of the identified habitats. Funding Italian Ministry of Health, grant number GR-2018-12365670; Italian Association for Cancer Research (grant IG 2014 Id.1524).
P10.11.B Re-sensitizing cancer cells to Tumor Treating Fields (TTFields) through PI3K/AKT/mTOR pathway inhibition
Authors: A Klein-Goldberg, T Voloshin, E Zemer-Tov, R Paz, L Koren, K Wainer-Katsir, C Wolfbauer, A Haber, M Giladi, U Weinberg, Y Palti
Journal: Neuro-Oncology (2022)

Abstract Background Tumor Treating Fields (TTFields) are alternating electric fields disrupting cellular processes critical for cancer cell replication and tumor progression. TTFields therapy is approved for treatment of newly diagnosed glioblastoma (GBM), recurrent GBM, and unresectable malignant pleural mesothelioma, and is currently under clinical investigation for treating other solid tumors, such as ovarian cancer, non-small cell lung carcinoma (NSCLC), and hepatocellular carcinoma (HCC). The research herein aimed to identify potential treatment escape mechanisms and explore the possibility of targeted inhibition of these pathways for re-sensitizing the cells to TTFields. Material and Methods GBM U-87 MG, ovarian A2780, and NSCLC H1299 cells were treated with TTFields (1.7 V/cm RMS, 200 or 150 kHz) for continuous long-term application (7 or 13 days, specific conditions depending on the cell line). Changes in signaling pathways in these cells relative to cells exposed to short term TTFields application (3 or 7 days, depending on cell line) were examined by Luminex multiplex assay. Specific pathway markers were examined by immunohistochemistry of tumor sections from sham or TTFields-treated rats bearing N1S1 HCC tumors. TTFields were then co-applied with relevant pathway inhibitors, followed by cell count measurements and western blot examinations for specific pathway markers. The concomitant application of TTFields with a selected inhibitor was tested in mice inoculated orthotopically with MOSE-L firefly luciferase (FFL) ovarian cancer cells. Tumor volume was measured at study end by luciferin signal detection using the In Vivo Imaging System (IVIS). Results Cancer cells exposed to long-term application of TTFields displayed decreased sensitivity to TTFields. The PI3K/AKT/mTOR pathway was activated in these cells, with significant increases in AKT and RPS6 phosphorylation levels also observed in HCC tumors from rats treated with TTFields. PI3K inhibitors re-sensitized the cells to TTFields cytotoxicity, with associated down regulation of AKT phosphorylation. Application of TTFields concomitant with the PI3K inhibitor alpelisib resulted in enhanced efficacy in the ovarian cancer mouse model. Conclusions The current research demonstrated that PI3K/AKT/mTOR signaling pathway activation was involved in the response to long-term application of TTFields, with increased phosphorylation of key proteins observed both in vitro and in vivo. Concomitant treatment with PI3K inhibitors and TTFields re-sensitized the cells to TTFields, as it alleviated TTFields-induced AKT activation.
P12.12.A Resolving the cellular architecture of infiltration zones in glioblastoma
Authors: M Ritter, C Blume, A Patel, P Sievers, H Dogan, C Herold-Mende, W Wick, A von Deimling, F Sahm
Journal: Neuro-Oncology (2022)

Abstract Background Therapy resistance and infiltration still pose major challenges in the treatment of glioma. In the tumour border niche, an interaction between different healthy cell types and malignant cells leads to therapy resistance, acquisition of stem-cell like features, and recurrence. However, studying the tumour border is quite challenging due to the lack of specific glioma markers. Although single cell datasets contain information about the abundance of different cell types, they still lack the spatial arrangement at the border niche. Spatial transcriptomic approaches might overcome these problems, but are still limited by a low resolution or a limited number of detectable transcripts. Material and Methods We applied the Visium spatial transcriptomics platform on 18 FFPE and 11 fresh frozen gliomas to image the cellular architecture of the tumour border niche. In addition, the transcriptome of single nuclei isolated from the fresh frozen sections was also analysed. Using Seurat and a single cell reference set from Darmanis et al. (2017) the cell types were mapped onto the section and the copy number variation profile (CNV) was determined. Results Using a single cell reference set we were able to map different cell types onto different areas of the tumour border niche of gliomas. To control the mapping the expression of cellular markers was used to detect healthy brain cells and the CNV profile was used to identify the tumour. The mapping matched the expression of markers and the CNV profile and only showed minor differences. First analysis confirmed distinct distribution of oligodendrocytes and neurons at the tumour border. We could not detect an enrichment of any tumour subtypes at the tumour border so far. However, one sample showed an enrichment of the mesenchymal subtype at the perinecrotic region. CNVs also showed low intratumoural heterogeneity for most sections. Conclusion Although the first results of the mapping of different cell types look promising, a larger reference set including a larger variety of cell types and tumour subtypes could improve the mapping even further. Nevertheless, we were able to show the cell type distribution at the tumour border and generate robust CNVs for most sections using spatial transcriptomics.
P17.11.A Experience of ketogenic diet with support of liquid formula 3:1 and high-grade gliomas: Case series
Authors: M I Zapata Laguado, A Luna-Meza, D Gonzalez Hurtado, L Aya Ramos
Journal: Neuro-Oncology (2022)

Abstract Background High-grade gliomas, including glioblastoma, are the most common primary malignant brain tumors in adults. Despite the efforts to develop new therapies, treatment options remain limited and the prognosis is poor. Ketogenic diet, is an emerging complementary therapy for high-grade gliomas. It is hypothesized that through the change of the energy source from glucose to ketones and the inability of glioma cells to metabolize ketone bodies with the same ease due to inefficient oxidative phosphorylation, tumor growth is slowed. The feasibility of a ketogenic diet is a matter of concern. Its influence on the quality of life of patients with advanced cancers showing that even though it may cause constipation and reflux, quality of life is generally not affected Material and Methods We reported a case series of patients with high-grade gliomas using ketogenic diet with liquid formula 3:1 ratio (KDS) as a complementary treatment. We describe baseline characteristics, and EORTC-QLQ30 score and symptom evaluation Results We describe the case of 3 patients (2 women and 1 man) with diagnoses of grade 4 glioblastoma (2) and grade 3 oligodendroglioma (1), mean age 46.7 years (38- 56 years), ECOG 1 (2) and ECOG2 (1), gross tumor resection (1 glioblastoma patient), subtotal resection (1 glioblastoma patient), and biopsy (1 oligodendroglioma patient). All patients received radiotherapy, 66.7% (n=2) stupp protocol, and 33.3% (n=1) received hypofractionated therapy and adjuvant treatment with temozolomide. All patients received first line with temozolomide, and 33.3% received a total of four lines of chemotherapy. All the patients were fed orally and managed with KDS at the last progression. Median follow up time was 4 months. KDS didn’t impact corporal weight and a positive impact was noted in seizure episodes (&amp;gt; 3 per day before vs &amp;lt; 3 per day after DKS) and quality of life (EORTC-QLQ30 61,3 [60 - 66,8] at the begining vs 70,9 [69,8 - 71,2] at the last visit). Regarding tolerance, one patient presented diarrhea and/or constipation grade 1 the first 5 days of treatment. Compliance was measured by days with a median adherence of 90%. Current disease status is stable disease (RANO criteria) in the three patients. Conclusion KDS could be an interesting therapy complementary to standard treatment in patients with high grade gliomas, especially in those patients who debut with seizures, improving quality of life and number of convulsive crises. More studies in adult patients are required to confirm this hypothesis
P09.01.A Speak up - a film project about living with a brain tumor
Authors: K Piil, M Mathiasen, I Raffnsøe, V Vollmer, K Risgaard
Journal: Neuro-Oncology (2022)

Abstract Background When a person is diagnosed with a brain tumor everyday life change completely. Patients experience severe and fluctuating symptoms and the relatives often become informal caregivers. Together they seek to manage the symptoms and maintain quality in daily living. Especially, cognitive impairments are difficult to manage and often associated with stigma. The purpose of this project was to create awareness and share knowledge about the challenges experienced by those living with a brain tumor and their informal caregivers. The creation of the films was chosen to be an appropriate medium to reach our targeted public population. Even though film cuts are time-consuming with several costs to produce, they have a beneficial perspective. Among the advantages of this media is that film cuts are easy to access and understand, simple to share on social media, and addresses universal and population-specific problems and concerns making the audience wide ranging. Thereby, the film cuts may help prevent prejudices and misunderstandings from arising, and also seek to provide patients with a language and courage to talk about difficult sensitive issues.The Danish Brain Tumor Association (Hjernetumorforeningen) has produced nine short films about being diagnosed with and living with a brain tumor diagnosis. We intend that the film cuts will support and inform patients, relatives/family, friends, and professionals to better understand the complex situations experienced by brain tumor patients. Material and Methods A screenwriter from The Ophelia School of Acting attended several network meetings held by the ‘Hjernetumorforeningen’ and interviewed patients, relatives, health care professionals and board members of ‘Hjernetumorforeningen’ to write the manuscript of each film. Patients and relatives were an ongoing active part of the development until the final product was agreed upon. Results In 2021, nine film cuts of 3-5 minutes premiered in an auditorium at the cinema Dagmar located in Copenhagen. Each film has a specific focus and outline complicated situations experienced from the time of being diagnosed to the establishment of having a new but changed everyday life: 1) A happy family, 2) The operation, 3) The message, 4) A new daily life, 5) Back to work, 6) Freja’s party, 7) Casework, 8) The family support group and 9) Talk about it. Conclusion The 9 short film cuts can be watched at The ‘Hjernetumorforeningens’ website, on YouTube, LinkedIn and on Facebook. The film cuts have gained international attention and can therefore be seen with English subtitles for international dissemination.
P11.36.A Could a transcriptome profile predict local control for glioblastoma?
Authors: G Antelo, I Valduvieco, S Comas, S Serrano, J Molero, C Balañá, S Villà, S Moreno, M Mollà, C Gomà
Journal: Neuro-Oncology (2022)

Abstract Background Glioblastoma (GB) is the most frequent and aggressive primary brain tumor in adults. The standard of care is surgery followed by radiotherapy in combination with temozolomide. GB molecular subtypes (Classical [CL], Mesenchimal [MES] and Proneural [PN]) have been correlated with prognosis. In the preclinical setting, CL and MES glioma stem-like initiating cells have also been shown to be more radioresistant than PN subtype. If confirmed in patients, the molecular subtype could predict the specific benefit of adjuvant treatment. The aim of this work is therefore to investigate whether GB molecular profiles are associated with treatment resistance in vivo. Material and Methods We analyzed the spatiotemporal pattern of recurrence (progression-free survival [PFS] and local control) in 37 GB patients treated with adjuvant radiotherapy (30 x 2 Gy, following EORTC contouring guidelines) plus temozolomide in the context of a multi-centric study. Relapse was defined following the RANO criteria (gadolinium enhanced area on MRI T1 sequence) and classified into 3 groups: in-field relapse (Dmean &amp;gt; 57 Gy), out-of-field relapse (Dmean &amp;lt; 48 Gy) and not-defined relapse (no follow-up MR data or marginal relapse). We used three different classification algorithms (SVM, K-Nearest Neighbor and single sample gene set enrichment analysis) for the transcriptomic classification of tumor samples, and we only assigned a molecular profile when all three classifications agreed, otherwise we called it Mixed profile. Patients with a not-defined spatial pattern of recurrence were included in the PFS analysis, but excluded from the local control analysis. Results The transcriptomic classification resulted in 14 CL, 1 MES, 9 PN and 13 Mixed. Median PFS after radiotherapy was 6 months, with a mean follow-up of 11 months. No differences in PFS were found between CL, PN and Mixed groups (the single MES case was excluded). Local control was analyzed in 24 patients (10 CL, 4 PN, 10 Mixed). Non- statistically significant differences were found between PN/Mixed and CL subtypes, with a median in-field relapse-free survival of 6.9 months (PN), 6.3 months (Mixed) and 4.7 months (CL). Conclusion Although there is no difference in PFS among GB molecular subtypes, these results suggest that the Classical subtypes seem to relapse faster inside the radiotherapy field. This would suggest a higher radioresistance compared to Proneural and Mixed subtypes, in agreement with preclinical data. Due to the low number of patients these differences are statistically non-significant, but they provide the rationale for further investigation in a larger patient cohort. Grant: Marató -TV3